Continuous Manufacturing

Benefits of converting

Batch to Continuous Processes

Dr Dimitrios I. Gerogiorgis

In stark contrast to most chemical process industries, where continuous manufacturing is the perennial standard, the pharmaceutical
industry has traditionally relied on batch processing for producing
innovative products of extreme added value and societal importance. For most other production supply chains, the low added
value between raw material and product prices and the increasing
cost of energy and labour necessitated high process efficiencies
early on. The vanishing comfort of high profits in pharmaceutical
markets has historically deterred the investment of effort in altering
organic products syntheses and the switch from batch to continuous processes. Pharmaceutical industry profit margins, however,
consistently diminish: R&D from initial discovery to product launch
is far more expensive and time-consuming, and further pressure is
induced by intense competition from generic manufacturers. A reevaluation of pharmaceutical process synthesis is thus essential,
and Continuous Pharmaceuticals Manufacturing emerges as a viable opportunity to streamline product development and simultaneously improve process economicst.
48

Chemical
Chemical Industry
Industry Digest.
Digest. July
July 2015
2015

Dr. Dimitrios Gerogiorgis is

a lecturer (Assistant Professor) in
Chemical Engineering at the Institute
for Materials and Processes of the
University of Edinburgh, focusing on
process systems modeling, design
and optimisation. As a Postdoctoral
Fellow at the Novartis-MIT Center
for Continuous Manufacturing (MA,
USA) he pioneered the modelbased development and systematic
evaluation of candidate continuous
pharmaceutical flowsheets, and
co-authored the first comparative economic evaluation of batch
vs. continuous pharmaceutical
manufacturing strategies. He has
published over 30 peer-reviewed
articles in journals and book series.

Continuous Manufacturing

ontinuous Pharmaceutical Manufacturing (CPM)

has a very strong potential to address pressing
profitability challenges but also ensure affordable
healthcare for growing populations. Continuous production methods can be scaled up faster and designed more
efficiently in terms of both solvent and energy use, thus
justifying the intense corporate interest demonstrated
by several recent investments in production-scale facilities. Exploring the constantly expanding limits of this
emerging technology is a high research priority: the literature abounds with candidate Active Pharmaceutical
Ingredients (API) whose continuous flow synthesis and
production-scale optimisation hold the key to success for
CPM.

Current Pharmaceutical Manufacturing

Pharmaceutical processes can be split into two major

stages, known as the primary (upstream) and secondary
(downstream) manufacturing: the former addresses production of the key molecule, known as the Drug Substance
(DS), while the latter focuses on delivering the final formulation, known as the Drug Product (DP). The Active
Pharmaceutical Ingredient (API) is the molecule with the
desired pharmacological effects: it is produced in bulk
through chemical or biological synthesis and purified via
physical unit operations (crystallisation, drying, milling)
and subsequently transferred to a secondary manufacturing facility, in which mixing one (or more) APIs with one
(or more) excipients yields the final product formulation.
Further physical processing (e.g. drying, size reduction/
enlargement, filtration, sterilisation) may be performed.
This final bulk product is then transformed into the final
marketable dosage form (most frequently tablets, but also
capsules, vials, tube/jar creams, aerosols) toward delivery
to the supply chain.
Successful CPM of organic intermediates and/or APIs
critically depends on technical advances in continuous
flow synthesis, flow chemistry understanding and equipment development. Cost issues which affect economic
viability are equally important though, governing how
CPM is evaluated with respect to potential change in the
industry (Behr, 2004).The economic viability of a drug
product is determined using a number of factors, e.g. the
total manufacturing cost, the selling price of the product,
the marketing costs, and in some cases, the product and/
or technology licensing costs. The key competitive edge
of pharmaceutical corporations has been R&D and innovation: as drug discoveries steadily decrease and the market share of generics increases constantly over the past 40
years, companies now strive to improve process economics in order to address a wide spectrum of threats and
survive such relentless globalised competition.

The gradual adoption of CPM concepts can

result in process economic gain: CapEx savings are attainable via fewer, smaller, cheaper equipment and reduced footprint, which
are direct effects of reaction telescoping and
novel process windows.
Batch synthesis of complex molecules at both laboratory and production scale is an arduous procedure,
in which long sequences of separate reactions are performed in large reactors, with purification steps conducted between successive stages. This normally effective
procedure is also extremely wasteful: the E-factor (wasteto-product ration) is as high as 25-100 for APIs, indicating
that 25-100 kg of waste are generated for every 1 kg of
complex molecule synthesised: the objective is thus not
only to reduce the total number of chemical synthesis
steps (reaction telescoping) but also improve individual
yields, if possible.
The overall yield achieved in product synthesis is a key
consideration in manufacturing economics. Traditionally,
the yield from batch processes is poor, due to non-uniform momentum, heat and mass transfer. A multi-stage
process comprising 10 stages (each with a yield of 50%) is
characterised by a very low overall yield of 0.1%. Raising
the yield of each stage to 80% would only result in an
overall yield of over 10%: the throughput is thus 100
times greater, necessitating smaller, less expensive equipment and reducing both capital (CapEx) and operating
expenditure (OpEx). Additionally, higher yields will result in lower solvent requirements and waste generation,
thereby ensuring further cost-savings.
Manufacturing cost is a function of the number of
synthesis steps: reducing the latter with more selective
reaction alternative simplies fewer purification steps
and more economical processes. Disruptive microreactor
technology enables previously unattainable syntheses,
which can now be implemented by employing novel process windows: allowing intensified process parameters
(concentration, pressure, temperature) flash chemistry,
in which hazardous reactions can be safely performed
and highly unstable intermediates can be used in flow
(Yoshida et al., 2008). Precise control of reaction residence
time (< 1 s) can induce higher selectivity, which in turn
has a direct bearing on production manufacturing cost:
fewer purification stages and less equipment expenditure
are required (lower CapEx), and less feedstock is wasted
to by-product (lower OpEx).
Process control and Process Analytical Technology

Chemical Industry Digest. July 2015

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Continuous Manufacturing
Continuous flow microreactors provide process intensification advantages (Losey
et al., 2001): high mixing efficiency, effective heat removal
and low process inventories
are key for very fast, exothermic and hazardous reactions.
Several continuous flow
Figure 1. Comparison of batch and continuous pharmaceutical manufacturing stage/resi- (tube-in-tube, packed bed,
microwave)microreactor
dence times for an API.
types are available, accomodating
biphasic
and
triphasic
reactions. Nevertheless, not
(PAT) are of high importance: continuous flow reacall
reactions
can
be
conducted
continuously: feedstocks,
tors exhibit high interfacial areas due to the formation
intermediates,
by-products
and
products must all be
of liquid layers that are only a few tens of micrometers
soluble
within
the
solvent,
and
well
away from the likely
thick, with surface-to-volume ratios as high as 40,000
precipitation
range
otherwise,
reaction
channels will be
m/m(considerably higher than the traditional 100-300
blocked,
with
catastrophic
reults.
Hydrogenations
are exm/m achieved in conventional stirred reactors). Very actremely
common
in
the
pharmaceutical
industry:
these
curate temperature control is thus attainable, and exothergas-phase
reactions
can
benefit
enormously
from
process
mic heat generated within the reactor can be dissipated
quickly. The conventional, off-line qualitative/quantita- intensification and the improved safety which is providtive analysis (QA)relies on time-consuming sequences of ed by microreactor technology (Johnson et al., 2012).
neutralisation, phase separation and laborious chromatographic/spectrometric analyses.

Batch processes are inherently labour-intensive due to

manual transportation of reactants to vessels for charging,
discharging of products, and cleaning of process equipment. Replacing a batch with a continuous process results
in very limited operator involvement, because only half
of the labour resources are required in the new paradigm
(Roberge et al., 2008).

Continuous Flow Synthesis

Common pharmaceutical syntheses include hydrogenations, nitrations, fluorinations, oxidations and organometallic reactions. Batch processes are hampered by
several disadvantages: limited heat removal, high residence times and vast solvent amounts used as heat sinks.

Nitrations depend on corrosive and explosive nitrating agents, being also prone to side reactions and waste
generation: continuous-flow microreactor technology
holds the promise of effective temperature control and
small reaction inventories. Minimisation of reaction runaway risks allows the reaction to propagate at higher temperatures (Burns & Ramshaw, 2002).
Halogenations are ideal candidates for implementation in continuous-flow microreactors (de Mas et al.,
2003): contacting gas and liquid phases can occur in tubein-tube microreactors, falling film microreactor and micro-bubble columns: in all cases, large surface areas maximise the contact between the two phases, thus increasing
mixing efficiency. Organometallic reactions entail the use
of highly unstable reagents: hence, theyare traditionally
conducted at extremely low temperatures, with slow addition of reagents to avoid temperature gradients and
possible thermal runaway within the reactor.
Time-consuming, laborious and expensive procedures threaten product
uniformity due to unacceptable variability; nevertheless, microreactors
can prevent off-spec production in quality-driven
industry (Loh et al., 2012;
Pedersen et al., 2013).

Figure 2. Comparison of solvent use and waste generation in batch and continuous pharmaceutical manufacturing.

50

Chemical Industry Digest. July 2015

A significant body of

Continuous Manufacturing

Continuous Manufacturing

literature details the quest for continuous production of

APIs and intermediates in order to replace batch with reliable, superior CPM processes. Several continuous flow
chemistry studies have been published, detailing the
production of molecules such as ibuprofen (Bogdan et
al., 2009), artemisinin (Lvesque & Seeberger, 2012) and
6-quinolone (Qian et al., 2010). A very extensive review
article illustrates CPM for a wide range of other APIs
(Malet-Sanz & Susanne, 2012).

Reaction Kinetics
Microreactors do not perform new chemistry, but enable better, reliable reaction control chemistry. Hence,
they are powerful tools for studying the intrinsic kinetics
of highly exothermic and mass-transfer controlled reactions: plug flow and high interfacial are aeliminate mass
transfer limitations, hot spots and concentration gradients
(routinely encountered in conventional reactors) which
that lead to suboptimal kinetic analyses. Zaborenko et
al. (2011) conducted a kinetic study of a model aminoalcohol formation by epoxide aminolysis, reporting that
a high pressure, high temperature microreactor enabled
rapid and efficient kine, which reduced the time needed
drastically for screening in comparison to carrying out
the kinetic study in a batch reactor. The reagent amount
required is drastically reduced, thus resulting in considerable savings. Due to the small reactor volumes, and the
rapid thermal control, many different experiments can be
run in quick succession in a wide range of concentrations,
residence times, and temperatures: the repercussions for
rapid process development and quicker release of a drug
to market are obvious. McMullen and Jensen (2011) used
an automated system for determining reaction kinetics,
consisting of a Si microreactor embedded in a computeraided experimentation framework for online kinetic parameter estimation via model-based optimisation.

Economic Analysis
Numerous research studies highlight the incontrovertible technical advantages of CPM over batch processes,
but to this day very few peer-reviewed publications have
quantitatively evaluated the projected economic performance benefits. Envisaging that the promise of higher
yields and selectivities will result in lower operating
(OpEx) and capital(CapEx) costs as a result of continuous operation is plausible, but a comparative evaluation
of options is not a trivial task.
Roberge et al. (2008) conducted an analysis of two different economic cases for a scaled-up reaction with an
organolithium intermediate, producing up to 700 kg of
product. The economic analysis did not address the process in its entirety (from raw materials to final product
Chemical Industry Digest. July 2015

51

Continuous Manufacturing

Figure 3. Process flow diagram for batch pharmaceutical manufacturing of an API (Schaber et al., 2011).

formulation). The first case studied represented the situation where an intermediate is produced in close proximity to raw materials, at the beginning of the synthetic
route. The second case studied a situation where the intermediate is produced further down, much closer to the
API, and economic benefits were identified by comparing
three process routes.
Schaber et al. (2011) investigated the economic impact
of operating a dedicated CPM plant using an organic key
intermediate (KI) and three organic reactions to derive
the API, toward subsequent tablet formation, at an annual blockbuster drug production scale (2000 tons) and several design parameters. The batch process was evaluated
against four different variations of the CPM process (with
and without recycle, and subsequent roller compaction/
RC or direct tablet formation/DTF). The economic evaluation was conducted with varying KI cost (100-3000 USD/
kg) and varying production yield (10% vs. the batch process), and varying API loading of the tablet DP (10 and
50 wt%). Process flow diagrams for batch and continuous
52

API manufacturing are presented in Figures 3 and 4, respectively.

The highest production cost reduction is obtained for a
switch from batch to CPM with recycle and DTF options.
Depending on KI production cost, total (CapEx+OpEx)
cost savings range between 9-40% when batch and CPM
yields coincide, but increase considerably (19-44%) if the
latter exceeds the former. Remarkably, total cost savings
are still achievable even for CPM yield which is lower
to that of the corresponding batch process, due to spectacular CapEx savings resulting from much smaller and
cheaper equipment. The OpEx savings result from decreased labour costs and lower water/solvent usage (61%
and 21%, respectively), the decreased time-to-market,
resulting from the ease of scale-up from laboratory-scale
to full manufacturing that results from the use of continuous-flow equipment.
Seifert et al. (2012) conducted an economic analysis
of modular CPM in comparison to multi-product batch
manufacturing plants, identifying that the former results

Chemical Industry Digest. July 2015

Continuous Manufacturing

Milling

Figure 4. Process flow diagram for continuous pharmaceutical manufacturing of an API (Schaber et al., 2011).

in a 30% Net Present Value (NPV) increase over the latter: a further 35% NPV increase was obtained under the
plausible assumption that construction can be completed
within one year.

Scale-Up
Due to slow product and process development, more
than half of the patent life can be lost before the drug
makes it to the market. Once the patent protection expires, the developer may lose up to 90% of market share
to generic manufacturers within 12 months (Plumb, 2005):
increasing the speed of delivery by decreasing R&D duration is hence paramount. Scale-up acceleration is thus
critical toward increasing profitability. There are significant problems in the scale-up of traditional batch vessels,
due to transport limitations in mixing, heat and mass
transfer. Microreactors escape many pitfalls, hence rapid
and efficient scaling up of novel pharmaceutical processes can benefit tremendously from their implementation
(Kockmann, 2011).
The production of pharmaceutical intermediates or
APIs can vary from a few mg(initial testing, pharmacokinetic studies), to hundreds of tons per year for a successful pharmaceutical blockbuster drug, Microreactors need
to flexible in terms of product output. The most probable
solution to dealing with such a large production range

lies within a modular design of reactor, where the mass

throughput can be increased by increasing the number of
parallel channels within the multi-channel microreactor,
or by using multiple microreactors. Poor material (esp.
solid) flow distribution over parallel channels is a serious problem, which can result in poor mixing, uneven
stoichiometry, localised heat loads, fouling and reaction
channel plugging. Symmetry-based hierarchical reactor
design (single-channel reactor, multi-channel plate reactor, microreactor stack, multiplestacks) offers a conceptual, highly efficient scale-up procedure which retains high
production-scale flexibility.
Microreactor scale-up must always consider operation
(residence) time. Increasing the inlet pressure allows for
greater pressure drop and higher flow rates along the microreactor, while increasing the cross-sectional area of reaction micro-channels can also accommodate higher flow
rates. Microreactor design optimisation is thus critical in
order to ensure that momentum, mass and heattransfer
processes serve simultaneously well the chemical reaction conducted. Mixing difficulties can be overcome by
increasing the pressure drop along the microreactor and/
or employing multiple reagent injection nodes, in order
to prevent hot spots by spreading reaction heat generation over a larger surface area. For higher capacity, increasing the channel size is favoured before resorting to

Chemical Industry Digest. July 2015

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Continuous Manufacturing
parallel operation of multiple reactor devices, due to the
technical issues at flow splitting and merging nodes, and
the expected impact on higher CapEx.

Conclusion
The benefits of continuous CPM over traditional batch
methods for manufacturing APIs and organic intermediates have been presented by examining in detail the economic impact, chemical synthesis, and available reactor
technology. Clearly, the gradual adoption of CPM concepts can result in process economic gain: CapEx savings
are attainable via fewer, smaller, cheaper equipment and
reduced footprint, which are direct effects of reaction
telescoping and novel process windows. Concurrently,
OpEx savings emerge due to increased productivity
(higher yield-selectivity), reduced manpower, utilities
and waste Microreactor use in CPM flowsheets enhances
heat, mass and momentum transfer efficiency, and enables the employment of intrinsically fast, exothermic,
and hazardous (e.g. Grignard, Reformatsky) reactions in
an inherently safe manner, so that reaction conditions are
reliably controlled, by-product formation is minimised,
and higher product quality is consistently achieved. By
using flash chemistry and novel process windows, process intensification can be achieved with high reliability
and versatility:synthetic routes for CPM of key intermediates and APIs can be telescoped, resulting in fewer
reaction and separation steps, and more profitable processes. Kinetic analyses, process modelling and simulation (Jolliffe & Gerogiorgis, 2015), scale-up and plant optimisation (Gerogiorgis & Barton, 2009) can be conducted
rapidly to accelerate R&D, reduce critical time-to-market,
and ensure the overall economic viability of the CPM process.

References
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Chemical Industry Digest. July 2015